In a surprising reversal of prevailing medical wisdom, researchers conducting a nationwide study of women's hormone replacement therapy have warned subjects taking estrogen that they are slightly more likely to have heart attacks, strokes or blood clots during the first two years of use.
Researchers have long assumed that estrogen helps protect women from cardiovascular problems. But the new findings appear to cast doubt on that assumption.
More than 27,000 participants in the Women's Health Initiative, a $700-million national study attempting to answer key questions about women's health, were notified of the discovery in letters mailed last Friday. The letters were sent after study officials noticed an increased risk in the first two years of the 15-year study.
While officials of the initiative described the new information as preliminary, it was unexpected and places new pressures on the government-funded study of a total of more than 160,000 women.
"It highlights how little we know about a subject that people think we know so much about," said Marcia Stefanick, principal investigator of the portion of the study based at Stanford Medical Center, one of about 40 study sites.
Nevertheless, Stefanick and others maintain that hormones may still be beneficial over the long term.
"It was unexpected to see an increase in cardiovascular events, but it doesn't mean the overall hypothesis is wrong," she said.
Experts further cautioned that the new information should not alter current recommendations and practices on hormone replacement therapy. They emphasized that the increased risk is seen only in the first two years of therapy and that the initiative is expected to yield a more precise picture of risks and benefits at its completion in 2005.
The increased risk did not meet statistical criteria for stopping the trial for safety reasons, federal officials said. But the initiative's Data and Safety Monitoring Board recommended that participants be informed of the finding and counseled about its meaning.
About 8.6 million post-menopausal American women take some combination of the sex hormones estrogen and progestin, and another 12 million who have had hysterectomies take estrogen alone.
Among the women taking hormones as part of the 15-year Women's Health Initiative, 16,609 are on estrogen and progestin and 10,739 are on estrogen alone. (Progestin, a synthetic form of progesterone, is given to women with a uterus to prevent uterine cancer.)
An increased risk of cardiovascular events was seen in both hormone groups, compared to women not taking hormones. The trend is less certain among the estrogen-only users because of the smaller number of women in that group.
Fewer than 1% of the women in either hormone group suffered a cardiovascular problem--a rate that is still less than the national average for U.S. women ages 50 to 79. But that was a higher rate than that of the control group.
Federal officials declined to release the actual number of cardiovascular problems.
"We are, unquestionably, dealing with a relatively small number of events, and there are not enough events to make any inferences with confidence," said Dr. David Herrington, a cardiologist at Wake Forest University School of Medicine.
However, study officials say they fear that participants may react badly to the news, dropping out of the trial and possibly leading to its early demise.
"This is just the first two years, and it's a very small risk. It took a study of 27,000 women to even find it," Stefanick said. "The question of long-term benefits is the one we're going after."
Dr. Jacques Rossouw, acting director of the Women's Health Initiative, said, "When the women were informed at the beginning of the study about the risks and benefits, we never anticipated there would be an early potential risk for cardiovascular disease. We have a contract with these women that said we'd tell them if something comes up that they need to know about."
Study officials said participants also are being told that the discovery mimics a 1998 study of women with existing heart disease. That study, called the Heart and Estrogen-Progestin Replacement Study (HERS), also showed a spike in the number of heart attacks among hormone users during the first year of use.
Both HERS and the preliminary Women's Health Initiative data indicate that the increased risk is highest in the first year of use and then begins to decline.
"The HERS study had a similar finding. So, just in case this isn't a wild coincidence, we felt, ethically, that we had to tell women about it," Rossouw said.
However, in a statement Monday, federal health officials noted: "Almost all [Women's Health Initiative] women have crossed the two-year mark or are about to do so; therefore thisinformation becomes available at a time when it no longer appears to be pertinent to the participants."
Previous studies have shown that estrogen improves cholesterol levels and increases the elasticity of arterial walls, which sparked the belief that it protects against cardiovascular disease.
While that still may be the case, some researchers now suggest that hormones could cause an inflammation of blood vessels in certain women.
"Recently, we've come to realize inflammation may play a very important role in the development of heart disease," Herrington said. "Although estrogen does have all these wonderful beneficial effects . . . it may be offset by this inflammation."
Future studies will try to identify whether certain women are susceptible to an increased risk of cardiovascular problems while taking hormones.
"Whatever this risk is, it seems to happen only at the beginning of hormone use, and it only happens to a small group of women," Stefanick said. "We don't have any idea right now about who these women are."